This invention provides an enzymatic process for preparing optically enriched intermediates useful in the preparation of substituted tricyclic compounds known as antihistamines and as inhibitors of farnesyl protein transferase (FPT). In particular, the process of this invention is useful in preparing intermediates useful in the preparation of FPT inhibitors disclosed, for example, in International Publication Number WO95/10516, published Apr. 20, 1995.
The use of enzymes for the synthesis of non-racemic chiral compounds is now well established. Since they are easy to use and readily available, hydrolases (proteases, esterases and lipases) have been used for the preparation of chirally pure molecules, under both aqueous and non-aqueous conditions. Enzyme catalyzed acylation reactions in non-aqueous solvents have been widely used for the kinetic resolution of racemic alcohols and amines. There are numerous examples in the literature of the selective acylation of a single enantiomer of a racemic primary amine: ##STR3## However, the enzymatic acylation of secondary and cyclic amines has been described less frequently: ##STR4## Most of the examples gleaned from the literature involve the acylation of chirally pure proline esters or amides catalyzed by alcalase (Chen et al, Biorg. Med. Chem. Lett., 4 (1994), p. 443), clostridiopeptidase B (Fortier et al, Biotechnol. Lett., 8 (1986), p. 777), .alpha.-chymotrypsin (Paradkar et al, J. Amer. Chem. Soc., 116 (1994), p. 5009), and aminoacyl-t-RNA synthetase (Nakajima et al, Int. J. Pept. Protein Res., 28 (1986), p. 1986). Examples illustrating the enzymatic acylation of chiral secondary amines are shown in the following reaction schemes: ##STR5##
______________________________________ PPL Catalyzed Acylation of 2-Hydroxymethylpiperidine Enzyme Temp .degree. C./Time h ees eep Conversion E ______________________________________ PPL RT/4 0.23 0.70 0.25 7 40/4 0.13 0.59 0.18 4 0-5/30 0.39 0.51 0.43 4 ______________________________________ (Asensio et al, Tet. Lett., 32 (1991), p. 4197). ##STR6##
______________________________________ Enzymatic Acylation of 3-Hydroxymethylpiperidine Vinyl Enzyme Acetate Time 2 3 Solvent mg/mmol equiv. h (Yield) (ee) (Yield) (ee) ______________________________________ Vinyl 300 50 91 29% (0.19) 69% (n/d) Acetate Acetonitrile 300 5 94 37% (&lt;0.02) 42% (n/d) CH.sub.2 Cl.sub.2 100 2.5 7.5 68% (0) -- ______________________________________ (Herradon et al, S. Synlett (1995), p. 599). ##STR7##
______________________________________ Product R % yield ee ______________________________________ 2a methyl 24 0.27 2b ethyl 31 0.31 2c Allyl 49 0.84 ______________________________________ Conditions: Substrate, 1 mmol; Carbonate, 1 mL; Enzyme, 20 mg; RT, 45 h. (Orsat, et al, J Amer. Chem. Soc., 118 (1996), p. 712). ##STR8## Generally, the resolutions suffer from low reactivity and/or selectivity. The reactions shown in schemes D and E probably occur by enzymatic acylation of the primary hydroxyl, followed by non-enzymatic intramolecular acyl transfer:
(In the above reaction Schemes A-H, the designation of the R substituents is for convenience in discussing those reactions, but does not correspond to the designation of the R substituents in the process claimed below.)